P1135: EFFECT OF GLUCARPIDASE RESCUE IN PATIENTS WITH HIGH-DOSE METHOTREXATE INDUCED ACUTE KIDNEY INJURY: A FRENCH PHARMACOVIGILANCE DATABASE STUDY
Authors: Sabrina Pierre, Maël Heiblig, Mikaïl Nourredine, Guillaume Grenet, Kevin Bihan, Thierry Vial
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: High-dose methotrexate (HD-MTX) remains the backbone treatment of various haematologic malignancies. Despite alkalinization, hydration and leucovorin rescue, delayed HD-MTX clearance and acute kidney injury (AKI) resulting in potential fatal toxicities continue to occur. Even though glucarpidase (GP) has been recently approved as a salvage therapy for delayed HD-MTX clearance, there is little evidence that reduction of plasma methotrexate concentrations is associated with a clinical benefit such as reduction of morbi-mortality and improvement in renal function. To our knowledge, there are only very few studies assessing the effect of GP on renal outcome. Aims: The main objective of this study was to evaluate the effect of GP on renal outcome in patients experiencing HD-MTX induced AKI. Methods: Spontaneous reports of HD-MTX induced AKI registered between 2015 and 2021 in the French Pharmacovigilance Database were extracted. Main clinical and biological data were collected, including renal function at day 7, which was the primary endpoint. AKI severity was defined as the lowest eGFR estimated before GP administration in patients receiving GP or within the first 72 hours of HD-MTX administration in those not receiving GP. Due to a large number of potential variables that could confound or mediate the causal effect of the use of GP on renal outcome, a directed acyclic graph (DAG) model was created to identified confounders. Based on this DAG model, we performed a mixed logistic regression with fixed effect of identified confounders: age, sex, estimated Glomerular Filtration Rate (eGFR) at baseline and post HD-MTX infusion, HD-MTX dose, preexisting AKI risks factors, infusion time and interacting drugs. Results: We identified 226 patients with HD-MTX induced AKI: 151 males and 75 females (sex ratio 1.9) with a median age of 60 years (range 13-88). At least one AKI risk factor was found in 58%. HD-MTX indication was lymphoma (n=151), leukemia (n=56), osteosarcoma (n=17), testicular cancer (n=1) and Richter’s syndrome (n=1). According to the eligibility criteria for GP administration as defined in the EMA glucarpidase summary of product characteristics (Voraxaze®), 113 (50%) patients were theoretically eligible of whom 90 received GP and 23 did not. Of the 113 (50%) ineligible patients, 56 (49.6%) received GP and 57 (50.4%) did not. Overall, 146 (64.6%) patients received GP (GP group) and 80 (35.4%) did not (NGP group). These two groups were comparable for sex ratio, age, body mass index (BMI), AKI risk factors, time to onset of toxicity, pre-MTX eGFR, interacting drugs and HD-MTX dose. GP group had significant higher MTX plasma concentrations at H24 and H48 and significant higher AKI severity. Renal function at day 7 after HD-MTX infusion was not statistically different between GP and NGP group (adjusted OR 1.00[0.36 -2.78], unadjusted OR 0.67[0.33-1.31]). The only variables influencing renal function at day 7 were baseline eGFR (OR 0.96, p=0.002) and AKI severity (OR 1.11, p<0.001). Noteworthy, there was no effect of HD-MTX dose nor interacting drugs on renal function at day 7. There was also no significant effect of GP on day 7 renal outcome in the restricted population of eligible patients. Summary/Conclusion: These results from a large retrospective study suggest that GP has no effect on day 7 renal outcome in patients experiencing HD-MTX induced AKI. Renal outcome at day 7 seems to be correlated to both baseline eGFR and AKI severity independently of GP rescue. Our data suggest that even GP lowers methotrexate plasmatic levels, it does not seem to improve renal outcome at day 7, thought it has no effect on intracellular methotrexate concentrations. Keywords: High dose methotrexate, Acute renal failure, Clinical outcome